Hypoglycemic drugs, circulating inflammatory proteins, and gallbladder diseases: A mediation mendelian randomization study

Zi-Qi Wang; Jin-Yan Zhang; Xingyao Tang; Jian-Bo Zhou

doi:10.1016/j.diabres.2024.111882

Hypoglycemic drugs, circulating inflammatory proteins, and gallbladder diseases: A mediation mendelian randomization study

Diabetes Res Clin Pract. 2024 Oct 2:217:111882. doi: 10.1016/j.diabres.2024.111882. Online ahead of print.

Authors

Zi-Qi Wang¹, Jin-Yan Zhang¹, Xingyao Tang², Jian-Bo Zhou³

Affiliations

¹ Beijing Tongren Hospital, Capital Medical University, Beijing, China.
² Capital Medical University, Beijing, China. Electronic address: txyhaitang@163.com.
³ Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China. Electronic address: jbzhou@ccmu.edu.cn.

PMID: 39366640
DOI: 10.1016/j.diabres.2024.111882

Abstract

Background: The relationship of hypoglycemic drugs, inflammatory proteins and gallbladder diseases remain unknown.

Methods: Four hypoglycemic drugs were selected as exposure: glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and metformin. The outcome were two gallbladder diseases: cholecystitis and cholelithiasis. Mendelian Randomization (MR) was employed to determine the association between hypoglycemic drugs and gallbladder diseases.

Results: DPP-4i and SGLT-2i had no effect on cholecystitis and cholelithiasis. However, a causal relationship was found between inhibition of ETFDH gene, a target of metformin expressed in cultured fibroblasts, and cholelithiasis (OR: 0.84, 95 %CI: (0.72,0.97), p = 0.021), as well as between GLP1R expression in the brain caudate basal ganglia and cholecystitis (OR: 1.29, 95 %CI: (1.11,1.49), p = 0.001). The effect of ETFDH inhibition on cholelithiasis through Interleukin-10 receptor subunit beta (IL-10RB) levels and Neurotrophin-3 (NT-3) levels, with a mediated proportion of 8 % and 8 %, respectively.

Conclusion: Metformin plays a protective role in cholelithiasis, while GLP-1RA have a harmful effect on the risk of cholecystitis. Metformin may reduce the risk of cholelithiasis by modulating the levels of Neurotrophin-3 (NT-3) and Interleukin-10 receptor subunit beta (IL-10RB). Further clinical and mechanistic studies are required to confirm these findings.

Keywords: Cholecystitis; Cholelithiasis; Glucagon-like peptide-1 receptor agonists; Hypoglycemic drugs; Inflammatory proteins; Mendelian Randomization; Metformin.